Response to: Efficacy of Brigatinib After Progression on Alectinib or Ceritinib: Does One Drug Work in a Pretreated Heterogeneous ALK-Positive NSCLC Population?
Authors: Sai-Hong Ignatius Ou, Edward S. Kim
Journal: Journal of Thoracic Oncology (2023)

We thank Dr. Urbanska for raising important points related to our study findings. We agree that the treatment of ALK-positive (ALK+) NSCLC is challenging and that it is important to further characterize optimal treatments for refractory ALK+ NSCLC on the basis of relevant biomarkers. Factors contributing to the complexity in identifying optimal treatments include the rarity of ALK+ NSCLC and difficulties in obtaining rebiopsy samples in patients who progress after first-line therapy. We also agree that the findings from ALK in Lung Cancer Trial of brigAtinib-2 (ALTA-2) do not address the molecular characterization of patients who respond to brigatinib in the second-line setting, because such characterization would have required patients to be enrolled on the basis of rebiopsy results after they progressed from first-line therapy. Characterization of the molecular determinants of clinical outcomes with brigatinib was an exploratory end point of ALTA-2. In ALTA-2, 100 of 103 total patients had baseline circulating tumor DNA (ctDNA) samples and 48 patients had end-of-treatment samples. Our clinical study team made great efforts working with the sites to collect tumor samples, but only five tumor samples were collected from patients who underwent rebiopsy after first-line therapy. Mutations detected in patients with ALK+ NSCLC who receive prior therapy are heterogenous, 1 Kang J. Chen H.J. Zhang X.C. et al. Heterogeneous responses and resistant mechanisms to crizotinib in ALK-positive advanced non-small cell lung cancer. Thorac Cancer. 2018; 9: 1093-1103 Crossref PubMed Scopus (17) Google Scholar , 2 Lin Y.T. Chiang C.L. Hung J.Y. et al. Resistance profiles of anaplastic lymphoma kinase tyrosine kinase inhibitors in advanced non-small-cell lung cancer: a multicenter study using targeted next-generation sequencing. Eur J Cancer. 2021; 156: 1-11 Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar , 3 Pailler E. Faugeroux V. Oulhen M. et al. Acquired resistance mutations to ALK inhibitors identified by single circulating tumor cell sequencing in ALK-rearranged non-small-cell lung cancer. Clin Cancer Res. 2019; 25: 6671-6682 Crossref PubMed Scopus (82) Google Scholar making it challenging to accrue an adequate number of samples to assess therapies in patients with specific baseline co-mutations in the second-line setting and beyond. Among ongoing biomarker-driven studies in patients with ALK+ NSCLC, the estimated time from study start to completion ranges from approximately 4 years to more than 7 years, underscoring the challenges in recruitment of this patient population. The design of clinical studies in patients with ALK+ NSCLC must be balanced between the feasibility of enrollment of patients with specific mutations and speed to obtain the answer to a clinical question. Efficacy of Brigatinib After Progression on Alectinib or Ceritinib: Does One Drug Work in a Pretreated Heterogeneous ALK-Positive NSCLC Population?Journal of Thoracic OncologyVol. 18Issue 3PreviewWe read with great interest the article by Ou et al.1 regarding the ALTA-2 study evaluating brigatinib in patients with advanced ALK-positive NSCLC and disease progression during alectinib or ceritinib treatment. The authors reported data from 103 patients receiving brigatinib as second (35 patients) or later-line (68 patients) with corresponding objective response rates of 20% and approximately 30%, respectively. The independent review committee's objective response rate for the whole group was 26.2%, and the median progression-free survival was 3.8 months. Full-Text PDF